N-sulfonyl-indole-3-acetamides

ABSTRACT

DERIVATIVES OF INDOLE-3-ACETAMIDE AND INDOLE-3-METHYLSULFONYL COMPOUNDS ARE PREPARED WHICH HAVE UTILITY AS SKELETAL MUSCLE STIMULANTS.

United States Patent Int. (:1. C07d 27/56 US. Cl. 260-32612 R 7 Claims ABSTRACT OF THE DISCLOSURE Derivatives of indole-3-acetamide and indole-3-methylsulfonyl compounds are prepared which have utility as skeletal muscle stimulants.

This invention is concerned with novel derivatives of indole that have utility as muscle stimulants. In particular the novel compounds have the following structural formula CHZR wherein R represents (1) CONHSO X, wherein X represents (a) lower alkyl of from 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl, either straight or branch chained, and either un substituted or substituted with halo such as chloro, bromo, or fluoro, or phenyl, (b) phenyl, either unsubstituted or substituted with (i) lower alkyl of 1 to 3 carbons,

(ii) di(lower alkyl)amino, wherein the lower alkyl groups have from 1 to 3 carbon atoms,

(iii) halo, such as chloro, bromo or fluoro,

(iv) nitro,

(v) lower alkoxy of from 1 to 3 carbon atoms, and

(vi) trifluoromethyl,

wherein R and R are the same or different and represent hydrogen, lower alkyl of 1 to 3 carbon atoms, phenyl-lower alkyl, or phenyl and when lower alkyl they can be joined together to form a heterocycle of 5-6 members with the nitrogen atom to which they are attached (2) -SO NH-R wherein R represents (a) hydrogen, (b) lower alkyl of from 1 to 6 carbon atoms,

wherein R represents (i) lower alkyl of 1 to 3 carbon atoms either unsubstituted or substituted with halogen such as chloro or fluoro, (ii) phenyl-lower alkyl, wherein the lower alkyl is of 1 to 3 carbon atoms, (iii) phenyl,

3,758,500 Patented Sept. 11, 1973 "ice /NH S/ wherein R represents lower alkyl of l to 3 carbon atoms;

p o (.JJNH(UJR wherein R represents (a) lower alkyl of 1 to 5 carbon atoms either straight or branch chained and either unsubstituted or substituted with such as (i) lower alkoxy of 1 to 3 carbon atoms, (ii) phenyl, either unsubstituted or substituted with halo, lower alkyl, or lower alkoxy, (b) phenyl, either unsubstituted or substituted with such as (i) lower alkyl of 1 to 3 carbon atoms, (ii) lower alkoxy of 1 to 3 carbon atoms, (iii) halo such as chloro, or bromo. R represents (1) hydrogen,

(2) lower alkyl of 1 to 3 carbons,

(3) lower alkenyl or from 3 to 5 carbon atoms, such as alkyl, bntenyl and the like;

R represents lower alkyl of 1 to 8 carbon atoms, either straight or branch chained and either unsubstituted or substituted with (a) lower alkoxy of 1 to 3 carbons,

(b) lower alkylthio of 1 to 3 carbons,

(c) halo, such as chloro, bromo, fluoro, dichloro,

trichloro, or trifluoro,

R is attached to either the 5- or 6-position of the indole nucleus and represents (1) hydrogen,

(2) lower alkyl of 1 to 3 carbon atoms,

(3) halo-lower alkyl, such as trifluorolower alkyl where the lower alkyl group has from 1 to 3 carbon atoms,

(4) halo such as chloro, bromo or fluoro,

(5) lower alkoXy-lower alkyl wherein the lower alkoxy and lower alkyl groups each has from 1 to 3 carbon atoms.

The active agents of this invention have been found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid extension of the legs when the animal is disturbed. The overt appearance is readily distinguishable from convulsions caused by central stimulation. The stimulation of striated muscle is useful in the treatment of disease entities characterized by progressive fatigability of the muscles such as myasthenia gravis.

Treatment with the active agents of this invention can be orally in the form of powders, granules, wafers, tablets, capsules or pills, or by injection intravenously, or intraperitoneally in suspension or in solution. The dose is from 1 to about 50 mg./ kg./ day either singly or on a multidose regimen depending on the severity of the disorder and the discretion of the physician.

The indole skeleton of the active compounds of this invention is prepared by standard chemical synthetic procedures well known in the art and are represented by the following reaction sequences:

wherein R and R are as previously defined, and R is other than chloro-, bromo-, dichloroor trichloro-lower alkyl.

When R is one of the polyhalogenated alkyls excepted from Method A above an alternate route to Compound I II is required in as much as the halogen group will not survive the very basic conditions provided by sodamide.

The alternate route to Compound III is represented by the following reaction sequence:

METHOD B o mon-r z-n R3 IV V The diazomethyl ketone (V), and an approximately equimol-ar amount of an acid catalyst such as boron trifluoride etherate or the hydrobromide salt of the aniline (IV) are mixed and an excess of the aniline (IV) is added. The mixture is then heated to 175200 C. for from 10 minutes to about 5 hours. The cooled mixture is neutralized and the excess aniline react-ant is separated by steam distillation or by extraction from ether solution with dilute acid. The product is then isolated by recrystallization from a suitable solvent.

The diazomethylketones are prepared by standard techniques involving the reaction of acid chlorides with diazomethane.

The substituents in the 3-position of the indole structure are introduced by a variety of reactions depending on the nature of the substituent.

The indole acetic acids and intermediates are prepared by known methods in accordance with the following reaction scheme:

METHOD C -H ECHO omNwm R: a

Hmong); N N

R2 I in R1 III VI CHaI KCN cnzooou KOH CHZCN R l R3 L 2 N R2 N R it in VIII VII The indole-3-acetic acid derivatives wherein R is monohalo-lower alkyl are prepared from Compound VII wherein R is benzyloxy-lower alkyl according to the following reaction:

BIETHOD D CH CN Hflpd cn on R3 OOH Ph Ra 2 N 2):: N 2)n VII(a) VII(b) (It =benzyloxy-lower alkyl) CHzCOOCHg CIIZOH CHZCN R R (cn2)Nx H01 \N 0112).):

(X =chloro or bromo) l VII(c) CHzCOOH \N/(CHQNX (R =halo-lower alkyl) VIII (a) Hydrogenolysis of the benzyl group of Compound VII(a) occurs readily in alcoholic solutions in the presence of a palladium catalyst to yield the corresponding 2-hydroxy-lower alkyl Compound VII(b). Halogenation of VII(b) with PCl or PBr by heating to about -150 C. in an inert organic solvent provides the halo-lower alkyl compound, VII(c). Alcoholysis of the nitrile VII(c) to the ester and hydrolysis with dilute hydrochloric provides the Z-halo-lower alkylindole-3-acetic acids VIII(a).

The compounds of this invention wherein R is CONHSO X are prepared by treatment of the acid chloride of an appropriately substituted indoleacetic acid with an alkali metal salt of a sulfonamide of Formula XSO NH as shown by the following reaction scheme:

METHOD E onzooon omooor R3 -6- R3 P 15 I N R \N/ R2 1'1 I'm vrn IX lxsoiNn ir OHZCONHSOZX Rs The acid chlorides of the indoleacetic acids are prepared by treatment of the indoleacetic acid in an inert organic solvent such as glyme, (1,2-dirnethoxyethane), diglyme, [bis-(Z-methoxyethyl)ether] or similar ether type solvents, with phosphorus pentachloride preferably at a low temperature i.e., from about 5 to about +l0 C. and preferably under an inert atmosphere. The acid chloride is not normally isolated as such but treated directly with an alkali metal salt, such as the potassium or sodium salt, of the appropriate sulfonamide preferably in the cold. After warming to room temperature the product is isolated by treatment with water and adjustment of the pH to between about 7 and 3 with a mineral acid such as hydrochloric, sulfuric, or the like. The alkali metal salt of the sulfonamides are prepared by treatment of the sulfonamide in an alcohol with an alkali metal tertiary alkoxide such as potassium t-butoxide.

In those instances wherein X represents and one or both of R and R is (are) benzyl, the benzyl group can be readily removed by hydrogenolysis, causing R and/or R to be hydrogen. Such a synthesis is represented by the following equation:

METHOD F ornc ONHS om L crnr'n CHICONHSOQNHR6 Compounds wherein R is SO NHR are prepared according to the following scheme:

In the preferred method the sodium indolemethanesulfonate is obtained by heating a mixture of an indole, sodium sulfite and formaldehyde in aqueous solution at from about 50 C. to reflux for from 10 to 24 hours. The product crystallizes on cooling. This sodium salt is then treated with phosphorus pentachloride in an inert organic solvent such as an ether in the cold. After stirring for 1 to about 5 hours the mixture is treated with an amine of formula R NH such as ammonia, methylamine or the like. The precipitated product is separated from inorganic materials by recrystallization from benzene.

Where R is acyl, i.e.

o y} .R1

the indolemethane-sulfonamide is acetylated by standard techniques with the appropriate acid chloride or anhydride. The reaction sequence is represented by the following equation:

METHOD H CHiSOqNH:

RICOCI R5 --0 R: N XIII (R'=H) 0 umsmNmLR N l XIV Where R represents i f t N the indolemethane-sulfonamide is treated with ethyl chlorocarbonate in refluxing acetone in the presence of an acid acceptor such as potassium carbonate for 12 to 24 hours. The resulting methanesulfonylcarbamate is then treated in the cold in an inert solvent such as glyme with an amine of formula I-INR R The reaction sequence is represented by the following equation:

METHOD J C H s OQNHQ O 0 01128 OgNH--O C Hs R2 N i s HN/ 0 /R cmsomniiN R2 R XVI Compounds wherein R represents NH E t are prepared according to the following equation:

METHOD K HCHO R R RwsE N N it it III XVII ll l 1 H CH, s -R CH; s R w R l t a 3: EN! R: N III/O l.

XIX XVIII The process for the preparation of these compounds comprises the reaction of an indole with a lower alkanethiol and formaldehyde in an inert solvent such as dioxane for about 10 to 24 hours to yield a lower alkylthiomethyl indole.

Oxidation of this intermediate with a suitable agent such as an alkali metal metaperiodate, lead tetraacetate, or permanganate at a temperature of 5-l0 C. for from to 24 hours produces the lower alkylsulfinylmethyl indole intermediate.

The above intermediate is then treated with concentrated sulfuric acid and hydrazoic acid at 40-45 C. After pouring on ice and extracting with an organic solvent, the lower a1kylsulfoximinomethylindole is obtained.

Compounds wherein R represents are prepared according to the following equation:

METHOD In CHICN CzHaOH R NBOCgHB N VII in NH (2 CH; OCzI*I5 a XX 1&

luwcoho O O CHgNH-E-R a R: N XXI U The appropriate indole-3-acetonitrile is treated with an alkali metal such as sodium or potassium in a lower alkanol usually ethanol at temperatures between ambient and the reflux temperature of the lower alkanol, preferably at about 50 C. for from 12 to about 48 hours, 24 hours usually being sufiicient. After evaporation of the alkanol solvent, the resulting imino ester residue is slurried in ether or other inert solvent and the mixture is treated with an acid anhydride at ambient temperature or with slight warming for 12 to about 48 hours. The reaction is then quenched by pouring into ice-water and the product is isolated by standard techniques from the organic layer.

8 EXAMPLE 1 Z-butyI-S-methylindole Step A.Preparatior1 of N-(2,4-dimethylphenyl)pentanamide: A solution of 22.7 g. (0.188 mole) of pentanoyl chloride in ml. tetrahydrofuran is added over 20 minutes to a stirred, ice-cooled solution of 121.2 g. (1 mole) 1-amino-2,4-dimethylbenzene. After standing for several hours at room temperature the solvent is removed by distillation in vacuo. The residue is taken up in ether and extracted with 12 N HCl to remove excess l-amino- 2,4-dimethylbenzene. After washing to neutrality and drying over magnesium sulfate, the ether solution is concentrated to yield 25.1 g. of N-(2,4-dimethylphenyl)pentanamide, M.P. l14ll5 C.

Step B.Preparation of 2-butyl-5-methylindole: To a stirred solution of 20.5 g. (0.1 mole) of N-(2,4-dirnethylphenyl)pentanamide in 250 m1. diethylaniline under nitrogen, is added in portions, 20 g. (0.526 mole) of sodamide. The mixture is heated slowly to 220 C. and maintained at this temperature for 5 hours. The reaction mixture is cooled to about 50 C., and the excess sodamide carefully decomposed by the addition of 300 ml. of water. The organic phase is extracted into 300 ml. ether and washed with portions of cold 4 N HCl and water. The ether solution is dried and concentrated to 20.2 g. of residual solid. Recrystallization from petroleum ether gives Z-butyI-S-methylindole, M.P. 73.5-75.5 C.

Employing the procedure of Example I, but substituting for the pentanoyl chloride and the 2,4-dimethylaniline used therein equivalent amounts of an acid chloride of formula R COCI and an aniline of structure CH3 R3 described in Table I there are produced the 1-R -2-R -R indoles also described in Table I.

TABLE I CH8 5 0 0 01 CH: R

r rr- R R O Example R R R n-CzHw H n-CaHP fi-CH; CHzOCHrfi-CHI CHaSCHz- H CFzCHz- H n-CzHrfi-GH: n-CaHr- G-CFa n-CaH1- B-CF; n-CaHr- 5-C1 n-OaH-r 5-01 Ill-0411a fi-CFa 4 0- fi-CHSO (CH2):- Q- 03,0 011,

EXAMPLE 15 2- (2,2-dichloroethyl) indole Step A.--Prepa.ration of diazomethyl 2,2-dichloroethyl ketone: A solution of 3,3-dichloropropionyl chloride (1.5 g., 0.01 mole) in ether 25 ml. is added dropwise to a rapidly stirred solution of diazomethane (0.03 mole) in 25 ml. ether at 0-5 C. The crude product is obtained by evaporation of the solvent and excess diazomethane and used directly in the next step.

Step B.Preparation of 2-(2,2-dichloroethyl)indole: A mixture of 1.0 g. of diazomethyl 2,2 dichloroethyl ketone, 1 g. of boron trifluoride etherate and 15 ml. of freshly distilled aniline is heated under reflux at 180 for 10 minutes. The cooled reaction mixture is treated with an excess of sodium carbonate solution and steam distilled to remove the aniline. The solid residue is collected and recrystallized from benzene-petroleum ether.

EXAMPLE 16 2- 2,2-trichloroethyl indole Employing the procedure of Example 15, but substituting for the 3,3-dichloropropionyl chloride used therein an equivalent amount of 3,3,3-trichloropropionyl chloride, there is produced 2-(2,2-trichloroethyl)indole.

EXAMPLE 17 2-butyl-5-methylindole-3-acetic acid Step A.--Preparation of 3-(dimethylaminomethyl)-2- butyl-S-methylindole: A solution of 6.087 g. (0.0325 mole) of 2-butyl-5-methylindole in 32.5 ml. dioxane is added dropwise to a stirred solution of 3.25 ml. of formaldehyde (25% aqueous), 7.15 ml. of dimethylamine (37% aqueous), 32.5 ml. of glacial acetic acid, and 32.5 ml. of dioxane at a temperature maintained below C. After the addition is complete, the reaction mixture is allowed to warm to room temperature over a period of 18 hours. It is diluted with 300 ml. water and filtered to remove a small amount of gummy byproduct. The filtrate is chilled in an ice-bath and made basic (pH 10- 11) with 10 N KOI-I. The precipitated product is filtered, washed with Water and dried. Recrystallization from nhexane gives 5.0 g. (63.3%) of 3(dimethylaminomethyl)- Step B.Preparation of 2 butyl 3-(cyanomethyl)-5- Z-butyl methylindole, M.P. 1085-1105 C. methylindole: A solution of 3.42 g. (0.014 mole) of 3- dimethylaminomethyl) 5 methyl 2 butylindole dissolved in 60 ml. dry ether is added dropwise with stirring to an ice-cooled solution of 19.5 ml. of iodomethane and stirred for 6 hours at 0 C. The precipitate is filtered, washed with ether and dried to yield 4.7 g. (87%) of the methiodide salt of 3 (dimethylaminomethyl) 5- methyl-2-butylindole.

Without further purification, the methiodide is added to a solution of 8.93 g. potassium cyanide in 68.3 ml. of water and maintained at 80 C. with stirring for 2 hours. After cooling, the reaction mixture is extracted with ether, the ether solution is washed with water, dried over magnesium sulfate and evaporated to a residual yellow oil, 2.9 g. (90%) of Z-butyl 3 (cyanomethyl)- S-methylindole.

Step C.-Preparation of 2-butyl 5 methylindole-3- acetic acid: The nitrile 2.9 g. (0.0128 mole), is added to a solution of 11.53 g. (0.205 mole) potassium hydroxide in 39 ml. of water and 64 ml. ethanol and refluxed for 16 hours under a blanket of nitrogen. The reaction mixture is diluted with 500 ml. water, acidified to pH 2 with concentrated hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to a crystalline residue, 3.1 g. (90%). Recrystallization from petroleum ether yields 2-butyl 5 methylindole 3 acetic acid, M.P. 106-110 C.

Employing the procedure of Example 17 as depicted by Method C, but substituting for the 2-butyl-5-methylindole used therein equivalent quantities of an indole of formula there are produced the substituted indoleacetic acids described in Table II.

TAB LE II CH2C O OH is 1 Example R R R n-CsH1 H n-CzH'r B-CH: 0 H30 (CH2)-- fi CHa C12CHCHr- H CH3s(CHz)- H ClaCCHr- H CFsCHr H n-CaHr 6-0111 n-CaH1 fi-CF; n-CaH1 5-CF; n-OaH1 n-CsH1 5-Cl 11-0411 5-C F3 11-C4Hs 5-CH30 (CHfl EXAMPLE 3 3 2-(2-chloroethyl)indole-3-acetic acid Step A.-Preparation of 2-(2-hydroxyethyl)indole-3- acetonitrile: A solution of 2-(2-benzyloxyethyl)indole-3- acetonitrile (1.0 g.) obtained as an intermediate in the synthesis of the compound of Example 32 in 35 ml. of ethanol is hydrogenated in the presence of a catalytic amount of 5% palladium on carbon. After separation of the catalyst by filtration, the filtrate is concentrated to dryness, and the residue of 2-(2-hydroxyethyl)indole-3- acetonitrile is collected and used directly in the next step.

Step B.Preparation of 2 (2 chloroethyl)indole-3- acetonitrile: 2-(2-hydroxyethyl)indole-3-acetonitrile (200 mg.), phosphorus trichloride (250 mg.) and 10 ml. of toluene are heated at reflux under nitrogen for 18 hours. The mixture is evaporated and the residue mixed with ice water and sodium carbonate. Extraction with chloroform provides the product, 2-(2-chloroethyl)indole-3- acetonitrile.

Step C.Preparation of methyl 2-(2-chloroethyl)indole-3-acetate: An ice cold solution of 2-(2-chloroethyl) indole-3-acetonitrile (220 mg.) in 5 ml. of methanol containing 0.05 ml. of water is saturated with hydrogen chloride gas. After stirring at room temperature for 48 hours the solution is evaporated to dryness, and the residue treated with sodium bicarbonate solution and then extracted with methylene chloride. Purification by chromatography on alumina yields methyl 2-(2-chloroethyl)indole-3-acetate.

Step D.-Preparation of 2 (2 chloroethyl)indole-3- acetic acid: Methyl 2 (2 chloroethyl)indole-3-acetate mg.) is hydrolyzed by refluxing in a mixture of 20 ml. benzene-10 ml. 10% hydrochloric acid for 3 hours. After cooling, the benzene layer is evaporated to dryness to yield 2-(2-chloroethyl)indole-3-acetic acid.

EXAMPLE 34 2-(2-bromoethyl)indole-3-acetic acid Employing the process of Example 33 but substituting for the phosphorus trichloride used therein an equivalent amount of phosphorus tribromide, there is produced 2-(2- bromoethyl)indole-3acetic acid.

1 1 EXAMPLE N- (methanesultonyl -5-methyl-2-propylindole- 3-acetamide Step A.--Preparation of potassium methanesulfonamide: A solution of 20.9 g. (0.22 mole) of methanesul- Employing the procedure of Example 35, the amide derivatives listed in Table III were prepared by substituting for the methane sulfonamide and S-methyl-Z-propylindole-3-acetic acid of Example 35, equivalent amounts of a reagent of formula NH SO X and 5- (or 6)-R -2R indole-3-acetic acid respectively.

TABLE III -CHzCOCl OHzCONHSOzX w u R3 l R2 $9 R KNH s 02X Example R R3 X M.P. C.)

36 Il-CsHv H C(Ha): 139-144.? 37 D-CsH1 H z 147-148 as n-Ca 1 H 113-121 39 n-O H1 5-CH: -CHF2 40 CHaO( 2)'-' 5-CHa Q 41 n-C H1 E-CHa a 42 c1 CHCHz- H z --N (CH3):

43 CH S CH H E Q F 45 Br 0H2) H 46 Cl OCH H 47 013 OH H 48 n-GaH1 5-CH:

-(CH3) CH2- 49 n-C H1 vii-CH3 r;

fonamide and potassium t-butoxide (24.68 g., 0.22 mole) EXAMPLE 50 in 450 ml. methanol is stirred for 2 hours at room temperature. The reaction mixture is then distilled to dryness and dried in high vacuum overnight.

Step B.Preparation of acid chloride of 5-methyl-2- propylindole-3-acetic acid: To a solution of 8.096 g. (0.035 mole) of 5-methyl-2-propyl-indole-3-acetic acid in dry glyme chilled to 0 to -5 C. under nitrogen, is added 7.291 g. (0.035 mole) of phosphorus pentachloride. The mixture is stirred for 2 hours by which time solution is complete.

Step C.-N-(methanesulfonyl) 5 methyl-Z-propylindole-3-acetamide: The above solution of the acid chloride is added to the potassium salt of methanesulfonamide from Step A and the reaction mixture allowed to warm to room temperature and stirred for 2 hours. Five hundred ml. of water is then added to the reaction mixture and the pH is adjusted to approximately 5 with dilute hydrochloric acid. The gummy solid which precipitates is extracted with ether, the ether extract washed with water, dried over magnesium sulfate, treated with charcoal and concentrated to a yellow oil which, on recrystallization from ether-petroleum ether yields 4 grams of product, M.P. 159159.5 C.

N- (methylsulfamyl -5-methyI-Z-propylindole- 3-acetamide EXAMPLE 51 5-methyl-2-propylindole-3-methanesulfonamide Step A.Preparation of sodium 5-methyl-2-propylindole-3-methanesulfonate: S-methyl-Z-propylindole (17.3 g., 0.1 mole) and sodium sulfite (50.4 g., 0.4 mole) are suspended in water (250 ml.) and heated to gentle reflux with stirring. Aqueous formaldehyde (25 ml. of 36.2%, 0.3 mole) is added and the mixture is refluxed for 18 hours. The reaction mixture is cooled and the product that crystallizes is collected by filtration and recrystallized from aqueous sodium bromide solution to give sodium 5-methyl-2-propylindole-3-methanesulfonate.

Step B.Preparation of 5-methyl-2-propylindole-3- methane sulfonamide: To a suspension of sodium 5- methyl-2-propylindole-3-methane sulfonate (14.5 g., 0.05 mole) in ethyl ether (250 ml.) at 5 C. is added phosphorus pentachloride (10.4 g., 0.05 mole) and the mixture is stirred for 2 hours. Maintaining the temperature of the reaction mixture at 0-5 C. ammonia gas (0.1 mole) is bubbled slowly into it. The precipitate consisting of sodium chloride, ammonium chloride and product is extracted several times with benzene. The extracts are concentrated to incipient cloudiness and then cooled to precipitate -methyl-2-propylindole-3-methanesulfonamide.

Employing the procedure of Example 51 but substituting for the 5-methyl-2-propylindole used in Step A and the ammonia used in Step B, equivalent amounts of 1-R 2-R -5 (or 6)-R indole and an amine of formula R NH respectively identified in Table IV, there are produced the N-R -1-R -2-R -5 (or 6)-indole-3-methanesulfonamides also identified in Table IV.

5-methyl-2-propylindole-3-methanesulfonacetamide 5 methyl 2 propylindole 3 methanesulfonamide (13.3 g., 0.05 mole) from Example 51 is refluxed in acetyl chloride ml.) for one hour. The excess acetyl chloride is removed by distillation in vacuo. The residue is treated with a large excess of water and the solid residue is col lected and dissolved in warm sodium bicarbonate solution. Acidification of the filtered solution with acetic acid causes precipitation of 5-methyl-2-propylindole-3-methanesulfonacetamide which is purified by recrystallization from aqueous ethanol.

Employing the process of Example 56 but substituting for the 5-methyl-2-propylindole 3 methanesulfonamide and the acetyl chloride utilized therein equivalent amounts of the 1-R -2-R -5(or 6)-R indole-3-methanesulfonamides and acyl chlorides of formula R COCl described in Table V, there are produced the 1-R -2-R -5 (or 6)-R indole 3 methanesulfonacylamides also described in Table V.

14 TABLE V CHgSOgNHg R RCOCl CH SO NHCOR N R2 t.

Example R R R R 57 CH3 n-osHz S-CF:

58 H3 11-04110 5-N02 Q 11-C3H1 5-CH3 --CH2CH2 n-CzH7 5 CH -C3 1 11-C H1 5-CF -OHC12 n-O H1 5-CH; CHF1 I1-C3H1 5-CH3 CF3 EXAMPLE 64 N- 5 -methyl-2-propylindole-3-methanesulfonyl -N-N'- dimethylurea Ethylchlorocarbonate (7.2 g., 0.066 mole) is added with stirring over a period of 3 hours to a mixture of S-methyl- 2-propylindole-3-methanesulfonamide (13.3 g., 0.05 mole) and anhydrous potassium carbonate in acetone (60 ml.). The mixture is stirred and refluxed for 18 hours, cooled and filtered. The solid residue is dissolved in water (150 ml.), filtered, and acidified with concentrated hydrochloric acid to Congo red which precipitates crude N-(S-meth'yl- 2-propylindole-3-methanesulfonyl)ethyl Carbamate intermediate. The precipitate is collected on a filter, Washed with water and dried. The sulfonylcar-bamate (16.9 g., 0.05 mole) is suspended in glyme (200 ml.), cooled to 0-5 C., and treated with dimethylamine (6.75 g., 0.15 mole). After warming to ambient temperature spontaneously, the solvent and excess amine are evaporated under reduced pressure and the residue is heated at C. at 5 mm. Hg for 6 hours. The residue is recrystallized from aqueous ethanol to give N-(S-methyl-Z-propylindole-3-methanesulfonyl)-N, -dimethylurea.

Employing the procedure of Example 64, but substituting for the S-methyl-Z-propylindole-3-methanesulfonamide and the dimethylamine utilized therein equivalent amounts of the 5 (or 6)-R -2-R -indole-3-methanesulonamides and the amines described in Table VI, there are produced the 5 (or 6)-R -2-R -indole 3 methanesulfonylureas also depicted in Table VI.

EXAMPLE 68 5-methyl-2-propyl-3-methylsulfoximinomethylindole Step. A.--Preparation of 5 methyl-2-propyl-3-methylthiomethylindole: A solution of 5-methyl-2-propylindole (17.3 g., 0.1 mole) in dioxane (100 ml.) is added dropwise with stirring to a solution of formaldehyde (25 ml., 25% aqueous) and methanethiol (10 g.) in dioxane (100 ml.) at 5 C. After addition is complete the reaction mixture is allowed to warm to ambient temperature over a period of 18 hours. Volatile materials are distilled in vacuo, and the residue is taken up in chloroform. After washing with Water and drying over magnesium sulfate, the chloroform solution is concentrated to a small volume and the solid residue of -methyl-2-propyl-3-methylthiomethylindole is collected by filtration.

Step B.Preparation of 5 methyl-2-propyl-3-methylsulfinylmethylindole: S-methyl-Z-propyl 3 methylthiomethylindole (23.3 g., 0.1 mole) from Step A is added to a 0.5 M solution of sodium metaperiodate (210 ml., 0.105 mole) at 0 C. The mixture is stirred at ice-bath temperature overnight. The precipitated sodium iodate is separated by filtration and the filtrate is extracted with chloroform. The extract is dried over magnesium sulfate and concentrated to dryness. The residue is recrystallized from acetone-ether to give 5-methyl-2propyl-3-methylsulfinylmethylindole.

Step C.-Preparation of 5 methyl-2-propyl-3-methyl sulfoximinomethylindole: S-methyl 2 propyl-3-methylsulfinylmethylindole (2.5 g., 0.01 mole) from Step B, is dissolved in ml. of chloroform and to the solution is added concentrated sulfuric acid (2.5 ml.). The mixture is warmed to 43 C., and hydrazoic acid (0.02 mole) in 10 ml. of chloroform is added dropwise over a period of 3 hours, and stirring is continued at this temperature for an additional 2 hours. The reaction mixture is poured into ice-water. The chloroform layer is separated. The aqueous layer is neutralized with aqueous sodium hydroxide solution and extracted with chloroform. The combined chloroform extracts are dried over magnesium sulfate and concentrated to dryness. The residue is recrystallized from low-boiling petroleum ether to give 5-methyl-2-propyl-3- methylsulfoximinomethylindole.

Employing the procedure of Example 68 but substituting for the 5-methyl-2-propylindole and methanethiol utilized therein, equivalent amounts of the 1-R -2-R -5 (or 6)- R -indoles and thiols of formula R Sl-l, described in Table 5-methyl-2-propylindole-3-N-acetylacetamide S-methyl-2-propy1indole-3-acetonitrile (2.12 gms.) in absolute ethanol (10 mls.) is added to sodium metal (.046 gms.) in absolute ethanol mls.). The reaction is warmed to 50 C. for 24 hours. When reaction is complete, the ethanol is evaporated in vacuo leaving a mixture of the imino ester and sodium ethoxide. To this residual mixture is added absolute ether (50 mls.), then acetic anhydride (3 mls.), and then the reaction is stirred at room temperature for 24 hours. The reaction mixture is poured onto ice-Water, stirred for 4 hours, and the ether TABLE VIII l /CH1CN /CHJJNHO R11 a I a z ARz Ex. R R2 R8 11 74 H CH3O(CH2) s-orr, 11-0311, 75 H CH3S(CHz)z- H -(CH2)2OCH3 76 H 11-03217 G-CH; -cm@ 71 H 11-0311 5-CF3 -(CHz)z-CH 7s H 11-0411. 5-CF3 CHz-OCH:

79 CH3- 11-03117 s-om (CHz)zl or so H n-C;H H

s1 H n-C H 5-01 -0H,

S2 H II-CqHn 5-CH3O(CH2)2 '2 -OC:H5

83 11 Il-C3H7 H 1 7 layer is then separated, washed with bicarbonate, dried, and evaporated in vacuo. The S-methyl-Z-propylindole-3- N-acetylacetamide is obtained by recrystallization from ethanol.

Employing substantially the procedure of Example 73 but substituting for the S-methyl-2-propylindole-3-acetonitrile and the acetic anhydride used therein the 1-R -2- R -(or 6)-R -indole-3-acetonitriles and acid anhydrides of formula (R CO) O described in Table VIII, there are produced the 1-R -2-R -5 (or 6)-R -indole-3-N-acetylacetamides also described in Table VIII.

The amount of muscle stimulant agent to be employed will depend upon the age, condition, weight, and other factors relevant to the animal to be treated and necessarily needs to be individualized by the physician or veterinarian for each patient. A suitable unit dosage form for oral administration is described in the following example.

EXAMPLE 84 Capsules containing 25 mgs. of active ingredient Mg. N (methanesulfonyl) 5 methyl-Z-propyl-indole- 3-acetamide 25 Corn starch U.S.P 10 Lactose U.S.P. 130

What is claimed is: 1. A compound of the structural formula 0 CHziLNHSOzX {,1 wherein R is hydrogen, or loweralkyl of 1-3 carbon atoms;

R is

loweralkyl of 1-8 carbon atoms, or a loweralkyl of 1-8 carbon atoms substituted with (a) loweralkoxy of 1-3 carbon atoms, (b) loweralkylthio of 1-3 carbon atoms, or (c) halo; R is either hydrogen, loweralkyl of 1-3 carbon atoms, haloloweralkyl of 1-3 carbon atoms, halo, or

loweralkoxy-loweralkyl in which both the loweralkoxy and loweralkyl groups have from 1-3 carbon 18 atoms, said R substituent being attached to either the 5- or -6-position of the indole nucleus; and X is loweralkyl of from 1-6 carbon atoms, haloloweralkyl of from 1-6 carbon atoms, phenylloweralkyl of from 7-12 carbon atoms, phenyl, 1-to-3-carbon alkylphenyl, di(loweralkyl of from 1-3 carbon atoms)-aminophenyl, halophenyl, nitrophenyl, 1-to-3-carbon alkoxyphenyl, trifiuorornethyl, or amino of the structure wherein R and R are members selected from the group consisting of hydrogen, loweralkyl of from 1-3 carbon atoms, phenyl-loweralkyl of from 7-12 carbon atoms, phenyl, or R and R when loweralkyl are joined together to form a 5-6 membered heterocycle with the nitrogen atom to which they are attached.

2. The compound of claim 1 wherein X is selected from the group consisting of loweralkyl, loweralkylphenyl, and NR R wherein R and R each represent loweralkyl.

3. The compound of claim 1 wherein R is selected from the group consisting of hydrogen and loweralkyl, R is loweralkyl, R is selected from the group consisting of hydrogen and loweralkyl, and X is NR R wherein R and R each represent loweralkyl.

4. N (methanesulfonyl) 5 methyl-Z-propylindole- 3-acetamide.

5. N (methanesulfonyl)-2-propylindole-3-acetamide.

6. N (p-methylphenylsulfonyl) 2 propylindole-3- acetamide.

7. N (dimethylaminosulfonyl) 2 propylindole-3- acetamide.

References Cited Smith, The Chemistry of Open-Chain Organic Nitrogen Compounds, vol. 1, p. 189 (1965).

JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R. 

